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Nuclear translocation of PTH receptor hijacks thyroid hormone signaling for bone mass regulation [RNA-seq]

ABSTRACT: After demonstrating that the bone-forming ability of mice is altered by blocking PTH1R entry into the nucleus, We performed RNA-seq on BMSCs from Pth1rΔNLS individuals and wild-type individuals to explore the mechanism behind this phenomenon.

ORGANISM(S): Mus musculus

PROVIDER: GSE233172 | GEO | 2023/12/20

REPOSITORIES: GEO

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Nuclear translocation of PTH receptor hijacks thyroid hormone signaling for bone mass regulation [ChIP-Seq]

Project description:After preliminary verification of physical interaction between PTH1R and THR, we next performed chromatin co-immunoprecipitation sequencing (ChIP -seq) to detect the overlapping downstream promoters genome-widely between PTH1R and THR.

2023-12-20 | GSE233174 | GEO

Nuclear translocation of PTH receptor hijacks thyroid hormone signaling for bone mass regulation

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-12-20 | GSE233176 | GEO

Nuclear translocation of PTH receptor hijacks thyroid hormone signaling for bone mass regulation

Project description:Nuclear translocation of PTH receptor hijacks thyroid hormone signaling for bone mass regulation

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Nuclear translocation of PTH receptor hijacks thyroid hormone signaling for bone mass regulation [RNA-seq]

Project description:Nuclear translocation of PTH receptor hijacks thyroid hormone signaling for bone mass regulation [RNA-seq]

| PRJNA975172 | ENA

Nuclear translocation of PTH receptor hijacks thyroid hormone signaling for bone mass regulation [ChIP-Seq]

Project description:Nuclear translocation of PTH receptor hijacks thyroid hormone signaling for bone mass regulation [ChIP-Seq]

| PRJNA975173 | ENA

Kindlin-2 modulates PTH1R to regulate bone mass and PTH actions in bone

Project description:Kindlin-2 modulates PTH1R to regulate bone mass and PTH actions in bone

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Parathyroid Hormone Receptor-1 Signaling Aggravates Hepatic Fibrosis through Upregulating cAMP Response Element Binding Protein-Like 2 (human)

Project description:Background & Aims Parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to skeletal development, bone turnover, and calcium homeostasis. However, the role of PTH1R signaling in liver fibrosis is largely unknown. Here, the role of PTH1R signaling in the activation of hepatic stellate cells (HSCs) and hepatic fibrosis was examined. Approach & Results PTH1R was highly expressed in activated HSCs and fibrotic liver by using human liver specimens or carbon tetrachloride (CCl4)-treated or methionine and choline-deficient diet (MCD)-fed C57/BL6 mice. The mRNA level of hepatic PTH1R was positively correlated to α-smooth muscle actin (α-SMA) in patients with liver cirrhosis. Mice with HSCs-specific PTH1R deletion were protected from CCl4, MCD, or western diet plus low-dose CCl4-induced liver fibrosis. Conversely, parathyroid hormone (PTH) aggravated liver fibrosis in CCl4-treated mice. Mouse primary HSCs and LX2 cell lines were used for in vitro experiments. Molecular analyses by luciferase reporter assays and chromatin-immunoprecipitation assays in combination with mRNA sequencing in HSCs revealed that cAMP response element-binding protein-like 2 (Crebl2), a novel regulator in HSCs treated by PTH that interacted with Mothers against decapentaplegic homolog 3 (SMAD3) and increased the transcription of transforming growth factor β (TGFβ) in activating HSCs and collagen deposition. In agreement, HSCs-specific Crebl2 deletion ameliorated PTH-induced liver fibrosis in CCl4-treated mice. Conclusions In both mouse and human models, we found that PTH1R was highly expressed in activated HSCs and fibrotic liver. PTH1R signaling regulated collagen production in the HSCs via Crebl2/SMAD3/TGFβ regulatory circuits. Blockade of PTH1R signaling in HSCs might help mitigate the development of liver fibrosis.

2023-03-29 | GSE227902 | GEO

Parathyroid Hormone Receptor-1 Signaling Aggravates Hepatic Fibrosis through Upregulating cAMP Response Element Binding Protein-Like 2 (mouse)

2023-03-29 | GSE227901 | GEO

Altered selectivity of parathyroid hormone (PTH) and PTH-related protein (PTHrP) for distinct conformations of the PTH/PTHrP receptor.

Project description:PTH and PTHrP use the same G protein-coupled receptor, the PTH/PTHrP receptor (PTHR), to mediate their distinct biological actions. The extent to which the mechanisms by which the two ligands bind to the PTHR differ is unclear. We examined this question using several pharmacological and biophysical approaches. Kinetic dissociation and equilibrium binding assays revealed that the binding of [(125)I]PTHrP(1-36) to the PTHR was more sensitive to GTPgammaS (added to functionally uncouple PTHR-G protein complexes) than was the binding of [(125)I]PTH(1-34) ( approximately 75% maximal inhibition vs. approximately 20%). Fluorescence resonance energy transfer-based kinetic analyses revealed that PTHrP(1-36) bound to the PTHR more slowly and dissociated from it more rapidly than did PTH(1-34). The cAMP signaling response capacity of PTHrP(1-36) in cells decayed more rapidly than did that of PTH(1-34) (t(1/2) = approximately 1 vs. approximately 2 h). Divergent residue 5 in the ligand, Ile in PTH and His in PTHrP, was identified as a key determinant of the altered receptor-interaction responses exhibited by the two peptides. We conclude that whereas PTH and PTHrP bind similarly to the G protein-coupled PTHR conformation (RG), PTH has a greater capacity to bind to the G protein-uncoupled conformation (R(0)) and, hence, can produce cumulatively greater signaling responses (via R(0)-->RG isomerization) than can PTHrP. Such conformational selectivity may relate to the distinct modes by which PTH and PTHrP act biologically, endocrine vs. paracrine, and may help explain reported differences in the effects that the ligands have on calcium and bone metabolism when administered to humans.

| S-EPMC2194631 | biostudies-literature

Negative regulation of parathyroid hormone (PTH)-activated phospholipase C by PTH/PTH-related peptide receptor phosphorylation and protein kinase A.

Project description:PTH binding to the PTH/PTHrP receptor activates adenylate cyclase/protein kinase A (PKA) and phospholipase C (PLC) pathways and increases receptor phosphorylation. The mechanisms regulating PTH activation of PLC signaling are poorly understood. In the current study, we explored the role of PTH/PTHrP receptor phosphorylation and PKA in PTH activation of PLC. When treated with PTH, LLCPK-1 cells stably expressing a green fluorescent protein (GFP)-tagged wild-type (WT) PTH/PTHrP receptor show a small dose-dependent increase in PLC signaling as measured by inositol trisphosphate accumulation assay. In contrast, PTH treatment of LLCPK-1 cells stably expressing a GFP-tagged receptor mutated in its carboxyl-terminal tail so that it cannot be phosphorylated (PD-GFP) results in significantly higher PLC activation (P<0.001). The effects of PTH on PLC activation are dose dependent and reach maximum at the 100 nm PTH dose. When WT receptor-expressing cells are pretreated with H89, a specific inhibitor of PKA, PTH activation of PLC signaling is enhanced in a dose-dependent manner. H89 pretreatment in PD-GFP cells causes a further increase in PLC activation in response to PTH treatment. Interestingly, PTH and forskolin (adenylate cyclase/PKA pathway activator) treatment causes an increase in PLCbeta3 phosphorylation at the Ser1105 inhibitory site and that increase is blocked by the PKA inhibitor, H89. Expression of a mutant PLCbeta3 in which Ser1105 was mutated to alanine (PLCbeta3-SA), in WT or PD cells increases PTH stimulation of inositol 1,4,5-trisphosphate formation. Altogether, these data suggest that PTH signaling to PLC is negatively regulated by PTH/PTHrP receptor phosphorylation and PKA. Furthermore, phosphorylation at Ser1105 is demonstrated as a regulatory mechanism of PLCbeta3 by PKA.

| S-EPMC2488210 | biostudies-literature

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